Abstract: Rheumatoid arthritis (RA) is a common, disabling and even fatal immune-mediated disease, in which the major manifestation is typically chronic, polyarticular synovitis that leads to destruction of cartilage and bone, with ensuing joint deformity and dysfunction. The long term goal of the proposed research is to better understand the pathogenesis of RA, in order to provide a scientific basis for more effective therapeutic interventions. An attractive framework for understanding RA synovitis involves consideration of the special juxtaposition of immune system cells, especially T lymphocytes, and resident tissue cells, notably fibroblast-like synoviocytes (FLS) that is characteristic of RA synovium. This application proposes renewal for five years of a research program that is focusing on the interactions between T cells and FLS, based on the hypothesis that the combination of direct cell-cell interactions and the effects of secreted T cell cytokines, primarily IL-17, profoundly influence joint inflammation and damage. Our work has shown that FLS can function as APCs, even for presentation of peptides from arthritogenic autoantigens to clonal T cell populations in an MHC- restricted manner. Moreover, we have demonstrated that T cells, activated in a manner that excludes T cell antigen receptor triggering, are potent effector cells for FLS activation. Molecules of emerging interest or importance in these interactions, based on recent work funded by this grant include: IL-17, secreted by a T cell subset recently determined to be unique and distinct;ligands of the T cell glycoprotein CD6, including a novel ligand that we have discovered: the B7-H3 molecule, the only member of the CD28 ligand family that is strongly expressed by FLS;and membrane-anchored TNF expressed by cytokine-activated T cells. In this renewal application we propose experiments that will provide a better understanding of the role of FLS in T cell responses to autoantigens and in control of effector T cell differentiation;as well as the role of B7-H3 and its receptor(s) on the T cell in interactions between T lymphocytes and non-classical APC such as FLS. We also have developed a novel monoclonal antibody that reacts with an FLS surface structure induced by IL-17 but not TNF, and have shown that this molecule is the ecto-N-aminopeptidase CD13. Experiments are proposed to determine the functional consequences of this effect of IL-17.Narrative: The relevance of this work to public health lies in its direct connection to RA, a common and serious disease that still lacks a defined etiology, a cure or a preventative strategy.